Significant advances in genetic technology have greatly facilitated our ability to discover novel biological systems. Although this progression continues at a rapid pace gaining a complete understanding of newly identified systems is sometimes hampered by a lack of appropriate pharmacological tools. Thus, our focus in this R21 application is to develop pharmacological tools for the recently discovered neuropeptide S receptor. [unreadable] [unreadable] Neuropeptide S (NPS) is a 20 amino acid peptide that has been linked via its cognate G-protein coupled receptor to a variety of disease states including anxiety, narcolepsy, asthma, obesity, and schizophrenia. Currently, there is a significant unmet need for non-peptide NPS molecular probes, particularly antagonists. Filling this void with potent and selective ligands will expedite discovery of potential therapies that act on the NPS receptor system. Moreover, unlike peptides, small organic molecules are more likely to be systemically bioavailable and penetrate the blood brain barrier. [unreadable] [unreadable] Our laboratory has invested in a program to identify non-peptide small molecules for the NPS receptor system. We have developed a rapid, plate-based functional assay and begun a medicinal chemistry program aimed at discovering non-peptide small molecules. Since initiating our program, we have identified an agonist lead scaffold and an antagonist lead scaffold. With this in mind, the goals of this R21 application are to further explore the structure-activity relationships of NPS ligands and to develop high affinity agonists and antagonists for the NPS receptor system. [unreadable] [unreadable] Our strategy utilizes computer modeling to integrate structural information from our in-house screening effort and homology based pharmacophore identification (vasopressin/oxytocin). We propose to synthesize new compounds using this knowledge in a weighted diversity approach rather than a general diversity screen. This approach will provide small molecule probes of NPS receptor function and may ultimately lead to drug-like entities capable of treating anxiety, narcolepsy, asthma, obesity, or schizophrenia. [unreadable] [unreadable] [unreadable]